Wortman Juliana C, Nahmad Marcos, Zhang Peng Cheng, Lander Arthur D, Yu Clare C
Department of Physics and Astronomy, University of California, Irvine, Irvine, California, United States of America.
Center for Complex Biological Systems, University of California, Irvine, Irvine, California, United States of America.
PLoS Comput Biol. 2017 Jul 3;13(7):e1005610. doi: 10.1371/journal.pcbi.1005610. eCollection 2017 Jul.
In developing tissues, cell polarization and proliferation are regulated by morphogens and signaling pathways. Cells throughout the Drosophila wing primordium typically show subcellular localization of the unconventional myosin Dachs on the distal side of cells (nearest the center of the disc). Dachs localization depends on the spatial distribution of bonds between the protocadherins Fat (Ft) and Dachsous (Ds), which form heterodimers between adjacent cells; and the Golgi kinase Four-jointed (Fj), which affects the binding affinities of Ft and Ds. The Fj concentration forms a linear gradient while the Ds concentration is roughly uniform throughout most of the wing pouch with a steep transition region that propagates from the center to the edge of the pouch during the third larval instar. Although the Fj gradient is an important cue for polarization, it is unclear how the polarization is affected by cell division and the expanding Ds transition region, both of which can alter the distribution of Ft-Ds heterodimers around the cell periphery. We have developed a computational model to address these questions. In our model, the binding affinity of Ft and Ds depends on phosphorylation by Fj. We assume that the asymmetry of the Ft-Ds bond distribution around the cell periphery defines the polarization, with greater asymmetry promoting cell proliferation. Our model predicts that this asymmetry is greatest in the radially-expanding transition region that leaves polarized cells in its wake. These cells naturally retain their bond distribution asymmetry after division by rapidly replenishing Ft-Ds bonds at new cell-cell interfaces. Thus we predict that the distal localization of Dachs in cells throughout the pouch requires the movement of the Ds transition region and the simple presence, rather than any specific spatial pattern, of Fj.
在发育中的组织中，细胞极化和增殖受形态发生素和信号通路调控。果蝇翅原基中的细胞通常在细胞远端（最靠近圆盘中心）呈现非常规肌球蛋白达克斯（Dachs）的亚细胞定位。达克斯的定位取决于原钙黏蛋白脂肪（Ft）和达克斯索斯（Ds）之间的键的空间分布，它们在相邻细胞间形成异二聚体；以及高尔基体激酶四关节蛋白（Fj），其影响Ft和Ds的结合亲和力。Fj浓度形成线性梯度，而Ds浓度在翅囊的大部分区域大致均匀，在第三幼虫龄期有一个从翅囊中心向边缘传播的陡峭过渡区。尽管Fj梯度是极化的重要线索，但尚不清楚细胞分裂和不断扩展的Ds过渡区如何影响极化，这两者都可改变细胞周边Ft-Ds异二聚体的分布。我们开发了一个计算模型来解决这些问题。在我们的模型中，Ft和Ds的结合亲和力取决于Fj的磷酸化作用。我们假设细胞周边Ft-Ds键分布的不对称性定义了极化，更大的不对称性促进细胞增殖。我们的模型预测，这种不对称性在径向扩展的过渡区最大，该区域身后留下极化细胞。这些细胞在分裂后通过在新的细胞-细胞界面快速补充Ft-Ds键，自然地保留其键分布的不对称性。因此我们预测，翅囊中细胞内达克斯的远端定位需要Ds过渡区的移动以及Fj的简单存在，而非任何特定的空间模式。
